Enhanced Antitumor Efficacy and Reduced Toxicity of Docetaxel Loaded Estradiol Functionalized Stealth Polymeric Nanoparticles

详细信息    查看全文

• 作者：Sanyog Jain ; Gollapalli Spandana ; Ashish Kumar Agrawal ; Varun Kushwah ; Kaushik Thanki
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：November 2, 2015
• 年：2015
• 卷：12
• 期：11
• 页码：3871-3884
• 全文大小：702K
• ISSN：1543-8392

文摘

In spite of extensive research over the decades, breast cancer treatment is still a major challenge due to nonspecific distribution of the chemotherapeutics. This void can be filled by restricting the distribution of chemotherapeutics toward the cancerous cells. In the present report estradiol (E₂) functionalization of docetaxel (DTX) loaded PLGA nanoparticles was supposed to have specific distribution of DTX to cancerous cells simultaneously avoiding the nonspecific distribution toward the normal cells. In line, E₂鈥揚EG-PLGA conjugate was synthesized and characterized by FTIR and NMR spectroscopy. Extensive optimization of different process variables resulted in the formation of spherical E₂鈥揚EG-PLGA NPs in the size range of 228.5 卤 11.8 nm and entrapment efficiency of 94.25 卤 2.49. Trehalose (5% w/v) resulted in the formation of a fluffy, easy to redisperse freeze-dried cake of nanoparticles. PXRD analysis revealed the amorphous nature of DTX encapsulated within the nanoparticles. X-ray photoelectron spectroscopy confirmed the presence of E₂ over the surface of nanoparticles. In line with our hypothesis, cellular uptake studies on ER positive MCF-7 cells revealed relatively higher uptake and efficient localization into the nuclear region of E₂鈥揚EG-PLGA NPs in comparison with plain counterparts, while in the case of ER negative HeLa cells E₂鈥揚EG-PLGA NPs showed no difference in fluorescence pattern as compared to MCF-7 cells incubated with unmodified nanoformulation, indicating nonspecific delivery of DTX. Moreover, MTT assay revealed relatively higher cytotoxicity of E₂鈥揚EG-PLGA NPs in comparison with free DTX. Furthermore, in vivo pharmacokinetic studies revealed 9.36- and 4.79-fold enhancement in circulation half-life and AUC_(0鈥撯垶), respectively, of E₂鈥揚EG-PLGA NPs in comparison with Taxotere. In vivo antitumor efficacy in DMBA induced rat model demonstrated significant reduction in tumor volume in comparison with the plain counterpart (PLGA-NPs) and a marketed formulation, Taxotere. Moreover, the safety of the estradiol functionalized PLGA NPs was confirmed by hepato- and nephrotoxicity studies.